No abstract

The ROS-based detection of the CNR effect revealed its dependence on the proton beam energy, dose and atomic Z value and provided insight into the low-linear energy transfer (LET) CNR radiation, suggesting that these factors may influence the therapeutic efficacy via chemical reactivities, transport behaviors, and intracellular oxidative stress.

Traversing proton beam-irradiated, mid/high-Z nanoparticles produce site-specific enhancement of X-ray photon-electron emission via the Coulomb nanoradiator (CNR) effect, resulting in a nano- to micro-scale therapeutic effect at the nanoparticle-uptake target site. Here, we demonstrate the uptake of iron oxide nanoparticles (IONs) and nanoradiator-mediated, site-specific thrombolysis without damaging the vascular endothelium in an arterial thrombosis mouse model. The enhancement of low-energy electron (LEE) emission and reactive oxygen species (ROS) production from traversing proton beam-irradiated IONs was examined. Flow recovery was only observed in CNR-treated mice, and greater than 50% removal of the thrombus was achieved. A 2.5-fold greater reduction in the thrombus-enabled flow recovery was observed in the CNR group compared with that observed in the untreated ION-only and proton-only control groups (p < 0.01). Enhancement of the X-ray photon-electron emission was evident from both the pronounced Shirley background in the electron yield and the 1.2- to 2.5-fold enhanced production of ROS by the proton-irradiated IONs, which suggests chemical degradation of the thrombus without potent emboli.

Background: Proton-impact metallic nanoparticles, inducing low-energy electrons emission and characteristic X-rays termed as Coulomb nanoradiator effect (CNR), are known to produce therapeutic enhancement in proton treatment on experimental tumors. The purpose of this pilot study was to investigate the effect of CNR-based dose enhancement on tumor growth inhibition in an iron-oxide nanoparticle (FeONP)-loaded orthotopic rat glioma model. Methods: Proton-induced CNR was exploited to treat glioma-bearing SD rat loaded with FeONP by either fully-absorbed single pristine Bragg peak (APBP) or spread-out Bragg peak (SOBP) 45-MeV proton beam. A selected number of rats were examined by MRI before and after treatment to obtain the size and position information for adjusting irradiation field. Tumor regression assay was performed by histological analysis of residual tumor in the sacrificed rats 7 days after treatment. The results of CNR-treated groups were compared with the proton alone control. Results: Intravenous injection of FeONP (300 mg/kg) elevated the tumor concentration of iron up to 37 μg of Fe/g tissue, with a tumor-to-normal ratio of 5, 24 hours after injection. The group receiving FeONP and proton beam showed 65% -79% smaller tumor volume dose-dependently compared with the proton alone group. The rats receiving FeONP and controlled irradiation field by MR imaging demonstrated more than 95% -99% tumor regression compared with MRI-determined initial tumor size. Conclusions: Proton-impact FeONP produced therapeutic enhancement compared with proton alone in an orthotopic rat glioma model at a selected temporal point after treatment. Single BP proton beam could induce CNRbased dose enhancement and produce enhanced tumor regression that was comparable to SOBP treatment despite inhomogeneous tumor dose in the APBP-treated tumor. These results may suggest emergence of novel Particle Induced Radiation Therapy (PIRT) on malignant glioma.